Background: We Investigated the role of tumor necrosis factor alpha (TNF-al
pha) in protamine-induced cardiotoxicity and the possibility of preventing
or decreasing this effect by anti TNF-alpha antibodies and heparin.
Methods: Isolated rat hearts were perfused for 60 min with Krebs-Henseleit
solution (KIT). The control group was perfused with KIT alone, the KIT > pr
otamine > KIT group was treated from the 20th to the 40th minute with prota
mine, and the KIT + anti-TNF > protamine + ainti-TNF > KH + anti-TNF group
was treated the same as the KH > protamine > KIT group but with anti-TNF-al
pha antibodies added throughout perfusion. The KIT + heparin > protamine heparin > KIT + heparin group was treated the same as the KH > protamine >
KH group but with heparin added to KH throughout perfusion. The KIT > prota
mine > KIT + heparin was perfused the same as the KH > protamine > KIT grou
p but with heparin added to KIT for the last 20 min. Left ventricular (LV)
function and coronary flow were measured every 10 min. TNF-alpha was measur
ed in the coronary sinus effluent. Left ventricular TNF messenger RNA was d
etermined in the control and KIT > protamine > KIT groups at baseline and a
fter the 40-min perfusion.
Results: Protamine caused a significant decrease of peak systolic pressure
and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the eff
luent in the KIT > protamine > KIT group (102.3 +/- 15.5 pg/min) and TNF me
ssenger RNA expression in left ventricular samples were detected. TNF-alpha
was below detectable concentrations in the control, KIT + anti-TNF > prota
mine + anti-TNF > KIT + anti-TNF, and KIT + heparin > protamine + heparin >
KH + heparin groups. TNF-alpha concentrations correlated with depression o
f LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the
increase of LV pressure (r = 0.976; P = 0.001). Heparin Improved LV recove
ry and decreased protamine-induced TNF-alpha release (KIT > protamine > KIT
+ heparin group).
Conclusions: Anti-TNF-alpha antibodies and heparin prevent protamine-induce
d TNF-alpha release and depression of LV function. Heparin Improves protami
ne-induced depression of cardiac function.